rs132630293

chrX-103789361-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000533.5(PLP1):c.725C>T(p.Ala242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,255 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A242P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PLP1 NM_000533.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.44

Genes affected

PLP1 (HGNC:9086): (proteolipid protein 1) This gene encodes a transmembrane proteolipid protein that is the predominant component of myelin. The encoded protein may play a role in the compaction, stabilization, and maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival. Mutations in this gene cause Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Alternatively splicing results in multiple transcript variants, including the DM20 splice variant. [provided by RefSeq, Feb 2015]

RAB9B (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000533.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant X-103789361-C-T is Pathogenic according to our data. Variant chrX-103789361-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11091.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLP1	NM_000533.5	c.725C>T	p.Ala242Val	missense_variant	6/7	ENST00000621218.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLP1	ENST00000621218.5	c.725C>T	p.Ala242Val	missense_variant	6/7	1	NM_000533.5	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095255 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 360685

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pelizaeus-Merzbacher disease, connatal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 03, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	23
Dann	Benign	0.35
DEOGEN2	Uncertain	0.63	D;D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;.;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	0.65	N;N;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.91	P;P;B
Vest4		0.36
MutPred		0.77		Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;
MVP		0.98
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.38
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs132630293; hg19: chrX-103044290;